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Thrombo-Inflammation in Preeclampsia and Pregnancy Induced Hypertension: Proteomics And Metabolomics Profiling of Platelets and Plasma Mediators

ABSTRACT: Background: Platelets may be pivotal mediators of the thrombo-haemorrhagic complications of preeclampsia (PE), linking inflammation and thrombosis with endothelial and vascular dysfunction. While gestational hypertension (GH) falls within the spectrum of hypertensive complications of pregnancy and is a risk factor for preeclampsia, it is unclear what biomarkers distinguish PE from GH. Aim: To identify specific plasma and platelet thrombo-inflammatory biomarkers indicative of preeclampsia and distinguish PE from GH. Methods: We performed multiplex immunoassays, assessed platelet and plasma proteomics and metabolomics data of PE patients, and compared with non-pregnant (NP), healthy pregnant (PC) and GH participants. Results: We report plasma proteins upregulated, enriched plasma metabolites and proteins distinctly overexpressed in platelets of PE and GH compared to NP and PC. Whilst procoagulation in PC may be fibrinogen driven, Inter-Alpha-Trypsin Inhibitors ITIH2 and ITIH3 were enriched in hypertensive complications of pregnancy (PE and GH), and fibronectin and S100A8/9 may be major procoagulant agonists in PE but not GH. In addition, platelet leucine-rich repeat-containing protein 27 and 42 (LRRC27/42) subunits of volume-regulated VRAC anion channels were markedly overexpressed in preeclampsia and may contribute to the heightened glucose sensitivity and the pro-thrombotic tendency of this disorder. Additionally, our multiplex immunoassays confirmed previous reports of increases in preeclampsia plasma cytokines, including SDF-1α, which can directly activate platelets; but also, i-309 and CTACK cytokines, whose effects on platelets we explored using STRING analysis. Conclusion: We identified biomarkers that may be monitored for preeclampsia onset and progression, and distinguish PE from GH. Also, through protein-protein interactions analysis, we generated a new hypothesis for platelets’ contribution to the thrombo-inflammatory states of preeclampsia.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Platelet, Blood Cell, Blood Plasma

DISEASE(S): Pre-eclampsia

SUBMITTER: Luiz Gustavo de Almeida

LAB HEAD: Dr. Antoine Dufour

PROVIDER: PXD031278 | Pride | 2022-03-16

REPOSITORIES: Pride

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			Action	DRS
	April_26_2021_plasma.zip	Other
	July__09_2021_platelet.zip	Other
	S11880_166_Ejaife_1_210422.raw	Raw
	S11881_167_Ejaife_2_210422.raw	Raw
	S11882_168_Ejaife_3_210422.raw	Raw

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Project description:Preeclampsia (PE) is a peculiar multisystemic disorder that contributes to maternal and perinatal morbidity. Exosomes, existing in the circulation, origin from late endosomes which are secreted into the extracellular surrounding by diverse cell types under different conditions, can mediate intercellular communication via transporting its constituents and regulate inflammation, immunomodulation and angiogenesis. We hypothesize that exosomes from trophoblast in preeclampsia complications under pathological hypoxia microenvironment impair vascular development by transmitting its contents to endothelial cells. Here, transwell and tube formation assays revealed that exosomes from hypoxic trophoblast cells attenuated the migration, and tube formation in human umbilical vein endothelial cells (HUVECs) in vitro. In a mouse model, hypoxic trophoblast cells derived exosomes leaded to vascular dysfunction and caused adverse PE-like birth outcomes. Next, we detected lncRNA expression in cord blood plasma derived exosomes from gestational age-matched preeclampsia and normal pregnancies by microarray analysis. Then, we identified the possible mechanisms of one up-regulated exosomal lncRNA, TINCR. Application of Quantitative RT-PCR, lncTINCR was confirmed overexpressing in exosomes released from cord blood plasma, peripheral blood plasma and human placental trophoblasts of preeclampsia patients. Moreover, the exosomal lncTINCR could be specifically secreted by hypoxic trophoblast cells and transferred to HUVECs, which increased autophagy in HUVECs and impaired angiogenesis of endothelial cells in vitro. Furthermore, we demonstrated that lncTINCR was considered as a competing endogenous RNA to regulate miR-424, which resulted in elevated ATG5 expression. Thus, we reported that exosomes intervened effective delivering of lncTINCR to endothelial cells to damage vascular functions and result in the development of PE. The newly identified exosomal lncTINCR /miR-424/ATG5 axis may present potential novel targets of diagnosis and treatment for PE. lncRNA profiles of cord blood plasma derived exosomes from gestational age-matched preeclampsia and normal pregnancies

Dataset Information

Thrombo-Inflammation in Preeclampsia and Pregnancy Induced Hypertension: Proteomics And Metabolomics Profiling of Platelets and Plasma Mediators

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